Levocetirizine hydrochloride & Ambroxol Hydrochloride modified release (5 mg +75mg)

Each modified release uncoated bilayered tablet contains:

Levocetirizine Hydrochloride IP 5 mg

(As immediate release)

Ambroxol Hydrochloride IP 75 mg

(As prolonged release)

Excipients q.s.

Colour: Sunset Yellow

Modified release uncoated bilayered tablet

5mg + 75mg

4.1 Therapeutic Indication

For symptomatic relief of productive cough associated with allergic rhinitis, when both antihistamine and mucolytic agents are desired.

4.2 Posology and method of administration

Adults and adolescents 12 years and above:1 tablet once a day

Elderly

Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment.

Renal impairment

The dosing intervals must be individualised according to renal function (eGFR – estimated Glomerular Filtration Rate). Refer to the following table and adjust the dose as indicated.

Dosing adjustments for patients with impaired renal function (as per Levocetirizine dose):

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient and his body weight. There are no specific data for children with renal impairment.

Hepatic impairment

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended (see Renal impairment above).

Method of administration - Oral

Tablet should be swallowed whole & not to be broken, crushed or chewed. It may be taken with or without food. It is recommended to take the daily dose in one single intake.

4.3 Contraindications

• Patients with history of hypersensitivity to any component of the product
• Hypersensitivity to the active substance, to cetirizine, to hydroxyzine, to any other piperazine derivatives or to any of the other excipients.
• Patients with end stage renal disease with eGFR below 10 ml/min (requiring dialysis treatment).
• Patients undergoing haemodialysis
• Children < 12 years of age

4.4 Special warnings and precautions for use

• Precaution is recommended with concurrent intake of alcohol.
• Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.
• Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.
• Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted.
• In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with Elriz XL.
• Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of Elriz XL.
• Concurrent use of Elriz-XL with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.
• The use of Elriz XL (Ambroxol) should be carefully considered in patients predisposed to peptic ulcers.
• Ciliary dyskinesia: In patients with ciliary dyskinesia the benefit of liquefaction of secretions should be carefully weighed against the risk of congestion of secretions.

Pediatric population

The use of ELRIZ®XL tablet is not recommended in children aged less than 12 years.

4.5 Drugs interactions

• No interaction studies have been performed with levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with anti-pyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.
• In vitro data indicate that levocetirizine is unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes.
• In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
• The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.
• In sensitive patients, the concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
• After administration of ambroxol concentrations of antibiotics (amoxicillin, cefuroxime, erythromycin) in broncho-pulmonary secretions and sputum is increased.
• Anti-tussives: Concomitant administration of anti-tussives may impair the expectoration of liquefied bronchial mucus due to inhibition of the cough reflex and cause congestion of secretions.

4.6 Use in special populations

Pregnancy

Caution is advised when Elriz-XL is used during pregnancy. Use during the first trimester of pregnancy is not recommended.

Breast-feeding

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.

Fertility

For levocetirizine no clinical data are available.

4.7 Effects on ability to drive and use machines

Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive. Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with levocetirizine.

Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account.

4.8 Undesirable effects

Levocetirizine

• Common adverse reactions with (≥1/100 to <1/10): Headache (3.2%), Somnolence (1.4%), dry Mouth (1.6%), and Fatigue (1.2%).
• The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1%) under compared to placebo (3.1%)
• Uncommon (≥1/1,000 to <1/100): asthenia or abdominal pain

Ambroxol

• Mild upper gastro-intestinal side effects primarily Taste disturbances, heartburn, dyspepsia, and occasionally nausea and vomiting have been reported.
• Allergic reactions have occurred rarely, primarily skin rashes.
• There have been extremely rare case reports of severe acute anaphylactic-type reactions but their relationship to Ambroxol is uncertain. Some of these patients have also shown allergic reactions to other substances.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: http://www.zuventus.co.in/safety.aspx

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Symptoms

Levocetirizine

• Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness.

Ambroxol

• There are no severe intoxications known following an overdose of Ambroxol. Manifestations that have been reported include short-term restlessness and diarrhoea. Consistent with the findings of preclinical studies, increased saliva production, nausea, vomiting, and a drop in blood pressure can be observed following extreme overdosing.

Therapeutic Measures: There is no known specific antidote. Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage may be considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by haemodialysis.

5.1 Mechanism of Action

Levocetirizine, the active enantiomer of cetirizine, is a second- generation anti-histamine and a potent and selective antagonist of peripheral H1-receptors.

Ambroxol is frequently used as mucolytic and it also induces the synthesis of surfactant in lung alveolar type II cells. By this mechanism, it decreases the work and effort of breathing and can improve respiratory symptoms. It has also been proved to have antioxidant and anti-inflammatory activities

5.2 Pharmacodynamic properties

At half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose. Levocetirizine shows receptor occupancy of 90% at 4 hours and 57% at 24 hours. The onset of action of levocetirizine 5 mg has been observed at 1-hour post drug intake.

Ambroxol is shown to exert several activities: i) secretolytic activity (i.e., promotes mucus clearance, facilitates expectoration, and eases productive cough); ii) anti-inflammatory and antioxidant activity; and iii) a local anesthetic effect through sodium channel blocking at the level of the cell membrane.

5.3 Pharmacokinetic properties

Levocetirizine exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects.

Pharmacokinetics in special Populations

• Elderly Levocetirizine dose should be adjusted in accordance with renal function in elderly patients
• Hepatic Insufficiency No dose adjustment is needed in patients with solely hepatic impairment.
• Renal Insufficiency Dosage and frequency of administration of ELRIZ®XL should be reduced
• Dosage and frequency of administration of Levocetirizine should be reduced in patients with mild, moderate or severe renal impairment
• In patients with moderate to severe renal / hepatic impairment, a slower elimination rate may lead to the accumulation of ambroxol and/or ambroxol-metabolites formed in the liver.

6.1 Animal Toxicology or Pharmacology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

ELRIZ®XL is a fixed dose combination of a Levocetirizine Hydrochloride (5mg) and Ambroxol Hydrochloride (75mg).

Levocetirizine hydrochloride is an orally active H1-receptor antagonist.

Molecular Formula: C₂₁H₂₅ClN₂O₃•HCl

Chemical name: (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid hydrochloride.

Molecular weight: 461.82

Molecular Structure:

Ambroxol is a metabolite of bromhexine and is widely used as a mucolytic.

Molecular Formula: C₁₃H₁₈Br₂N₂O.HCl

Chemical name: trans-4-((2-amino-3,5-dibromobenzyl) amino) cyclohexanol hydrochloride

Molecular Weight: 414.56 g/mol

Molecular Structure:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

10 blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store in cool, dry and dark place.
• Keep out of reach of children.

• ELRIZ®XL Tablet should be swallowed whole & not to be broken, crushed or chewed.
• Somnolence Caution patients against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of levocetirizine dihydrochloride.
• Concomitant Use of Alcohol and other Central Nervous System Depressants Instruct patients to avoid concurrent use of levocetirizine hydrochloride with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.
• Dosing of Tablets Do not exceed the recommended daily dose in adults and adolescents 12 years of age. Advise patients to not ingest more than the recommended dose of levocetirizine hydrochloride because of the increased risk of somnolence at higher doses.
• Do not take this medicine, if you are allergic to Levocetirizine and/or Ambroxol Signs of an allergic reaction include a rash, itching or shortness of breath.
• Advice patients to talk to your doctor or pharmacist, if you get any side effects. This includes any possible side effects not listed in this leaflet.
• Advice patients If they have any further questions, ask doctor or pharmacist.

Levocetirizine Tablets IP 5 mg

Each film coated tablet contains

Levocetirizine Hydrochloride IP 5 mg

Excipients q.s.

Colour: Titanium Dioxide IP

Film-coated tablet. 5 mg

Therapeutic Indication

For allergic rhinitis and chronic urticaria.

Posology and method of administration

• Adults and adolescents 12 years and above:

The daily recommended dose is 5 mg (1 tablet).

Elderly

Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment.

Renal impairment

The dosing intervals must be individualised according to renal function (eGFR – estimated Glomerular Filtration Rate). Refer to the following table and adjust the dose as indicated.

Dosing adjustments for patients with impaired renal function:

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient and his body weight. There are no specific data for children with renal impairment.

Hepatic impairment

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended (see Renal impairment above).

Paediatric population

Children aged 6 to 12 years:

The daily recommended dose is 5 mg (1 film-coated tablet).

For children aged 2 to 6 years no adjusted dosage is possible with the film-coated tablet formulation. It is recommended to use a paediatric formulation of Elriz.

Method of administration

The film-coated tablet must be taken orally, swallowed whole with liquid and may be taken with or without food. It is recommended to take the daily dose in one single intake.

Duration of use:

Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less than four weeks a year) has to be treated according to the disease and its history; it can be stopped once the symptoms have disappeared and can be restarted again when symptoms reappear. In case of persistent allergic rhinitis (symptoms experienced for more than four days a week or for more than four weeks a year), continuous therapy can be proposed to the patient during the period of exposure to allergens.

There is clinical experience with the use of levocetirizine for treatment periods of at least 6 months. In chronic urticaria and chronic allergic rhinitis, there is clinical experience of use of cetirizine (racemate) for up to one year.

Contraindications

Hypersensitivity to the active substance, to cetirizine, to hydroxyzine, to any other piperazine derivatives or to any of the other excipients.

Patients with end stage renal disease with estimated Glomerular Filtration Rate (eGFR) below 15 ml/min (requiring dialysis treatment).

Special warnings and precautions for use

Precaution is recommended with concurrent intake of alcohol.

Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.

Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.

Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted.

Paediatric population

The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of Elriz.

Drugs interactions

No interaction studies have been performed with levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.

In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.

The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.

In sensitive patients, the concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

Use in special populations

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or feto/ neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal development

The use of levocetirizine may be considered during pregnancy, if necessary.

Breast-feeding

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.

Fertility

For levocetirizine no clinical data are available.

Effects on ability to drive and use machines

Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive.

Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account.

Undesirable effects

Clinical studies

Adults and adolescents above 12 years of age

In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in the levocetirizine 5 mg group had at least one adverse drug reaction compared to 11.3% in the placebo group. 91.6 % of these adverse drug reactions were mild to moderate.

In therapeutic trials, the dropout rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.

Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the medicinal product at the recommended dose of 5 mg daily. From this pooling, following incidence of adverse drug reactions were reported at rates of 1% or greater (common: ≥1/100 to <1/10) under levocetirizine 5 mg or placebo:

Further uncommon incidences of adverse reactions (uncommon ≥1/1,000 to <1/100) like asthenia or abdominal pain were observed.

The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1%) under levocetirizine 5 mg than under placebo (3.1%).

Paediatric population

In two placebo-controlled studies in paediatric patients aged 6-11 months and aged 1 year to less than 6 years, 159 subjects were exposed to levocetirizine at the dose of 1.25 mg daily for 2 weeks and 1.25 mg twice daily respectively. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

In children aged 6-12 years double blind placebo controlled studies were performed where 243 children were exposed to 5 mg levocetirizine daily for variable periods ranging from less than 1 week to 13 weeks. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

Post-marketing experience

Adverse reactions from post-marketing experience are per System Organ Class and per frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

• Immune system disorders: Not known: hypersensitivity including anaphylaxis
• Metabolism and nutrition disorders: Not known: increased appetite
• Psychiatric disorders: Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare
• Nervous system disorders: Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia
• Ear and labyrinth disorders:Not known: vertigo
• Eyes disorders: Not known: visual disturbances, blurred vision, oculogyration
• Cardiac disorders: Not known: palpitations, tachycardia
• Respiratory, thoracic and mediastinal disorders: Not known: dyspnoea
• Gastrointestinal disorders: Not known: nausea, vomiting, diarrhoea
• Hepatobiliary disorders: Not known: hepatitis
• Renal and urinary disorders: Not known: dysuria, urinary retention
• Skin and subcutaneous tissue disorders: Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticarial
• Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia
• General disorders and administration site conditions: Not known: oedema
• Investigations: Not known: weight increased, abnormal liver function tests
• Description of selected adverse reactions After levocetirizine discontinuation, pruritus has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Overdose

Symptoms

Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness.

Management of overdoses

There is no known specific antidote to levocetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage may be considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by haemodialysis.

Mechanism of Action

Levocetirizine hydrochloride, the active enantiomer of cetirizine, is a second-generation anti-histamine and a potent and selective antagonist of peripheral H1-receptors.

Pharmacodynamic properties

Pharmacotherapeutic group: antihistamine for systemic use, piperazine derivatives, ATC code: R06A E09.

Binding studies revealed that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 min.

After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.

Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.

The pharmacodynamic activity of levocetirizine has been studied in randomised, controlled trials:

In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamine-induced wheal and flare, levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post drug intake in placebo controlled trials in the model of the allergen challenge chamber.

Clinical efficacy and safety

The efficacy and safety of levocetirizine has been demonstrated in several double-blind, placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic rhinitis, perennial allergic rhinitis, or persistent allergic rhinitis. Levocetirizine has been shown to significantly improve symptoms of allergic rhinitis, including nasal obstruction in some studies.

Chronic idiopathic urticaria was studied as a model for urticarial conditions. Since histamine release is a causal factor in urticarial diseases, levocetirizine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria.

ECGs did not show relevant effects of levocetirizine on QT interval.

Pharmacokinetic properties

The pharmacokinetics of levocetirizine are linear with dose- and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.

Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.

Distribution

No tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain-barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the CNS compartment.

In humans, levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Biotransformation

The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O- dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose.

Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances, or vice-versa, is unlikely.

Elimination

The plasma half-life in adults is 7.9 ± 1.9 hours. The half-life is shorter in small children.

The mean apparent total body clearance in adults is 0.63 ml/min/kg. The major route of excretion of levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

Animal Toxicology or Pharmacology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Levocetirizine dihydrochloride, the active component of Elriz tablets and oral solution, is an orally active H1‑receptor antagonist. The chemical name is (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C21H25ClN2O3•2HCl. The molecular weight is 461.82

Chemical structure is shown below:

Incompatibilities

Not applicable.

Shelf-life

Refer on the pack

Packaging information

2 Composite blister strips of 5 x 10 tablets each

Storage and handing instructions

• Store protected from light & moisture at a temperature not exceeding 30°C.
• Keep out of reach of children.

Somnolence

Caution patients against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of levocetirizine dihydrochloride.

Concomitant Use of Alcohol and other Central Nervous System Depressants

Instruct patients to avoid concurrent use of levocetirizine hydrochloride with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.

Dosing of Levocetirizine hydrochloride Tablets

Do not exceed the recommended daily dose in adults and adolescents 12 years of age and older of 5 mg once daily in the evening. In children 6 to 11 years of age the recommended dose is 2.5 mg once daily in the evening. Advise patients to not ingest more than the recommended dose of levocetirizine hydrochloride because of the increased risk of somnolence at higher doses.

Do not take this medicine, if you are allergic to levocetirizine

Signs of an allergic reaction include a rash, itching or shortness of breath.

Advice patients to talk to your doctor or pharmacist, if you get any side effects. This includes any possible side effects not listed in this leaflet.

Advice patients If they have any further questions, ask doctor or pharmacist.

Levocetirizine syrup

Each 5 ml syrup contains:

Levocetirizine Hydrochloride 2.5 mg

Excipients …………………. q.s.

In a flavored syrup base.

Oral syrup, Levocetirizine 2.5mg/5ml

4.1 Therapeutic Indication

For allergic rhinitis and chronic urticaria.

4.2 Posology and method of administration

Adults and adolescents 12 years and above:

The daily recommended dose is 5 mg (10 ml of solution).

Elderly

Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment.

Renal impairment

The dosing intervals must be individualised according to renal function (eGFR – estimated Glomerular Filtration Rate). Refer to the following table and adjust the dose as indicated.

Dosing adjustments for patients with impaired renal function:

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient and his body weight. There are no specific data for children with renal impairment.

Hepatic impairment

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended (see Renal impairment above).

Paediatric population

Children aged 6 to 12 years:

The daily recommended dose is 5 mg (10 ml of solution).

Children aged 2 to 6 years:

The daily recommended dose is 2.5 mg to be administered in 2 intakes of 1.25 mg (2.5 ml of solution twice daily).

Even if some clinical data are available in children aged 6 months to 12 years, these data are not sufficient to support the administration of levocetirizine to infants and toddlers aged less than 2 years.

Method of administration

An oral syringe is included in the package. The appropriate volume of oral solution should be measured with the oral syringe, and poured in a spoon or in a glass of water. The oral solution must be taken orally immediately after dilution, and may be taken with or without food.

Duration of use:

Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less than four weeks a year) has to be treated according to the disease and its history; it can be stopped once the symptoms have disappeared and can be restarted again when symptoms reappear. In case of persistent allergic rhinitis (symptoms experienced for more than four days a week or for more than four weeks a year), continuous therapy can be proposed to the patient during the period of exposure to allergens.

There is clinical experience with the use of levocetirizine for treatment periods of at least 6 months. In chronic urticaria and chronic allergic rhinitis, there is clinical experience of use of cetirizine (racemate) for up to one year.

4.3 Contraindications

Hypersensitivity to the active substance, to cetirizine, to hydroxyzine, to any other piperazine derivatives or to any of the other excipients.

Patients with end stage renal disease with estimated Glomerular Filtration Rate (eGFR) below 10 ml/min (requiring dialysis treatment).

4.4 Special warnings and precautions for use

Precaution is recommended with concurrent intake of alcohol.

Elriz contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.

Elriz contains maltitol liquid

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.

Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.

Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted.

Pediatric population

Even if some clinical data are available in children aged 6 months to 12 years, these data are not sufficient to support the administration of levocetirizine to infants and toddlers aged less than 2 years.

4.5 Drugs interactions

No interaction studies have been performed with levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.

In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.

The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.

In sensitive patients, the concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

4.6 Use in special populations

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or feto/neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal development.

The use of levocetirizine may be considered during pregnancy, if necessary.

Breast-feeding

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.

Fertility

For levocetirizine no clinical data are available.

4.7 Effects on ability to drive and use machines

Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive and use machines.

Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account.

4.8 Undesirable effects

Clinical studies

Adults and adolescents above 12 years of age In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in the levocetirizine 5 mg group had at least one adverse drug reaction compared to 11.3% in the placebo group. 91.6 % of these adverse drug reactions were mild to moderate. In therapeutic trials, the dropout rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo. Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the medicinal product at the recommended dose of 5 mg daily. From this pooling, following incidence of adverse drug reactions were reported at rates of 1% or greater (common: ≥ 1/100 to < 1/10) under levocetirizine 5 mg or placebo:

Further uncommon incidences of adverse reactions (uncommon ≥ 1/1000 to < 1/100) like asthenia or abdominal pain were observed.

The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1%) under levocetirizine 5 mg than under placebo (3.1%).

Paediatric population

In two placebo-controlled studies in paediatric patients aged 6-11 months and aged 1 year to less than 6 years, 159 subjects were exposed to levocetirizine at the dose of 1.25 mg daily for 2 weeks and 1.25 mg twice daily respectively. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

In children aged 6-12 years double blind placebo controlled studies were performed where 243 children were exposed to 5 mg levocetirizine daily for variable periods ranging from less than 1 week to 13 weeks. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

Post-marketing experience

Adverse reactions from post-marketing experience are per System Organ Class and per frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

• Immune system disorders:Not known: hypersensitivity including anaphylaxis
• Metabolism and nutrition disorders: Not known: increased appetite
• Psychiatric disorders:Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare
• Nervous system disorders: Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia
• Ear and labyrinth disorders: Not known: vertigo
• Eyes disorders: Not known: visual disturbances, blurred vision, oculogyration
• Cardiac disorders: Not known: palpitations, tachycardia
• Respiratory, thoracic and mediastinal disorders:Not known: dyspnoea
• Gastrointestinal disorders: Not known: nausea, vomiting, diarrhoea
• Hepatobiliary disorders: Not known: hepatitis
• Renal and urinary disorders: Not known: dysuria, urinary retention
• Skin and subcutaneous tissue disorders: Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticarial
• Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia
• General disorders and administration site conditions: Not known: oedema
• Investigations: Not known: weight increased, abnormal liver function tests
• Description of selected adverse reactions After levocetirizine discontinuation, pruritus has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

Symptoms

Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness.

Management of overdoses

There is no known specific antidote to levocetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage may be considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by haemodialysis.

5.1 Mechanism of Action

Levocetirizine hydrochloride, the active enantiomer of cetirizine, is a second-generation anti-histamine and a potent and selective antagonist of peripheral H1-receptors.

5.2 Pharmacodynamic properties

Pharmacodynamic effects

The pharmacodynamic activity of levocetirizine has been studied in randomised, controlled trials:

In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamine-induced wheal and flare, levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post drug intake in placebo controlled trials in the model of the allergen challenge chamber.

In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability and a decrease in eosinophil recruitment.

Clinical efficacy and safety

The efficacy and safety of levocetirizine has been demonstrated in several double-blind, placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic rhinitis, perennial allergic rhinitis, or persistent allergic rhinitis. Levocetirizine has been shown to significantly improve symptoms of allergic rhinitis, including nasal obstruction in some studies.

A 6-month clinical study in 551 adult patients (including 276 levocetirizine-treated patients) suffering from persistent allergic rhinitis (symptoms present 4 days a week for at least 4 consecutive weeks) and sensitized to house dust mites and grass pollen demonstrated that levocetirizine 5 mg was clinically and statistically significantly more potent than placebo on the relief from the total symptom score of allergic rhinitis throughout the whole duration of the study, without any tachyphylaxis. During the whole duration of the study, levocetirizine significantly improved the quality of life of the patients.

In a placebo-controlled clinical trial including 166 patients suffering from chronic idiopathic urticaria, 85 patients were treated with placebo and 81 patients with levocetirizine 5 mg once daily over six weeks. Treatment with levocetirizine resulted in significant decrease in pruritus severity over the first week and over the total treatment period as compared to placebo. Levocetirizine also resulted in a larger improvement of health-related quality of life as assessed by the Dermatology Life Quality Index as compared to placebo. Chronic idiopathic urticaria was studied as a model for urticarial conditions. Since histamine release is a causal factor in urticarial diseases, levocetirizine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria.

ECGs did not show relevant effects of levocetirizine on QT interval.

5.3 Pharmacokinetic properties

The pharmacokinetics of levocetirizine are linear with dose- and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.

Absorption

Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.

Distribution

No tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain-barrier.

In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the CNS compartment. In humans, levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Biotransformation

The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and Odealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose. Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances, or vice-versa, is unlikely.

Elimination

The plasma half-life in adults is 7.9 ± 1.9 hours. The half-life is shorter in small children.

The mean apparent total body clearance in adults is 0.63 ml/min/kg. The major route of excretion of levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

6.1 Animal Toxicology or Pharmacology

No carcinogenicity studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies are relevant for determination of the carcinogenic potential of levocetirizine. In a 2-year carcinogenicity study, in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults, approximately 10 times the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 15 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m2 basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults, approximately 4 times the maximum recommended daily oral dose in children 6 to 11 years of age, and approximately 6 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m basis). No increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults, equivalent to the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 2 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m2 basis). The clinical significance of these findings during long-term use of levocetirizine dihydrochloride is not known.

Levocetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in mice. In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the recommended daily oral dose in adults on a mg/m² basis)

Levocetirizine dihydrochloride, the active component of Elriz oral solution, is an orally active H1‑receptor antagonist.

The chemical name is (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties.

The empirical formula of levocetirizine dihydrochloride is C₂₁H₂₅ClN₂O₃•2HCl.

The molecular weight is 461.82

Chemical structure is shown below:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

A bottle of 30 ml

8.4 Storage and handing instructions

Store below 25°C. Protect from light.

Somnolence

Caution patients against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of levocetirizine dihydrochloride.

Concomitant

Use of Alcohol and other Central Nervous System Depressants Instruct patients to avoid concurrent use of levocetirizine hydrochloride with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.

Dosing of Levocetirizine hydrochloride syrup

Do not exceed the recommended daily dose. Advise patients to not ingest more than the recommended dose of levocetirizine hydrochloride because of the increased risk of somnolence at higher doses.

Do not take this medicine, if you are allergic to levocetirizine

Signs of an allergic reaction include a rash, itching or shortness of breath.

Advice patients to talk to your doctor or pharmacist, if you get any side effects. This includes any possible side effects not listed in this leaflet.

Advice patients if they have any further questions, ask doctor or pharmacist.

30.08.2024

Efonidipine Hydrochloride Ethanolate Tablets 10 mg / 20 mg / 40 mg

EFNOCAR-10

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 10 mg

Excipients q.s.

Colour: Titanium Dioxide IP

EFNOCAR-20

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 20 mg

Excipients q.s.

Colour: Titanium Dioxide IP

EFNOCAR-40

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 40 mg

Excipients q.s.

Colour: Titanium Dioxide IP

Film coated tablet

10/ 20/40 mg

4.1 Therapeutic Indication

Efonidipine is indicated for the management of

• Essential hypertension and renal parenchymal hypertension
• Angina

4.2 Posology and method of administration

Adults

• Essential hypertension and renal parenchymal hypertension: 20-40 mg orally once daily. A dose of up to 80 mg/day has been reported to be safe and effective in clinical trials.
• Angina: 40 mg/day.

Elderly

Efonidipine should be started with a low dose (20mg/day) and the patient's condition should be monitored. The dose should be halved in case the patient is intolerant to the higher dose.

In Children

Efonidipine is not recommended in infants and children as safety is not established in this group of patients.

4.3 Contraindications

• In patients with known hypersensitivity to Efonidipine or any other component of the formulation
• In pregnant women

4.4 Special warnings and precautions for use

• Should be administered with caution in patients with hepatic impairment.
• Should be administered with caution in patients with low BP and/or sinus node dysfunction.
• The drug should be withdrawn gradually to prevent rebound hypertension or worsening of angina.
• Administration of the drug may cause hypotension. Under such circumstances appropriate measures should be taken to either reduce the dose or withdraw the drug.
• Should not be taken with grapefruit juice as there may be excessive lowering of blood pressure.
• Dizziness may occur while taking antihypertensive agents. Hence, working on aerial platform, working with dangerous machinery and/or driving should be avoided.
• To be sold by retail on the prescription of Cardiologist / Nephrologist / Endocrinologist and Specialist in General / Internal medicine / Critical Care medicine only.

4.5 Drugs interactions

Concomitant administration of other antihypertensive agent/s may enhance the antihypertensive effect of efonidipine.

• Administration of calcium channel blockers (CCBs) with Cimetidine may cause elevated levels of CCBs.
• Increased levels of CCBs observed when taken concomitantly with grapefruit juice which may result in excessive lowering of blood pressure.
• Efonidipine when taken along with Tacrolimus may cause increased blood levels of Tacrolimus.

4.6 Use in special populations

Pregnancy

Efonidipine should not be administered in pregnant women.

Nursing Mothers

Efonidipine should not be administered in lactating women.

4.7 Effects on ability to drive and use machines

If patients taking Efonidipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

4.8 Undesirable effects

The common side effects are hot flushes, palpitations, facial flushing and headache. In addition, elevation in serum total cholesterol, ALT (SGPT), AST (SGOT) and BUN may occur.

Tabulated list of adverse reactions

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Reporting of suspected adverse reactions

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to:medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

In humans, experience with intentional overdose is limited. The stomach should be emptied by aspiration and gastric lavage if the patient reports immediately or up to two hours after overdosage.

Clinically significant hypotension due to Efonidipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

5.1 Mechanism of Action

Efonidipine, a new generation dihydropyridine (DHP) calcium channel blocker, inhibits both L-type and T-type calcium channels.

5.2 Pharmacodynamic properties

• Efonidipine exhibits antihypertensive effect through vasodilatation by blocking L-type and T-type calcium channels.
• Efonidipine has a negative chronotropic effect. Working on sino atrial node cells by inhibiting T-type calcium channel activation, Efonidipine prolongs the late phase-4 depolarization of the sino atrial node action potential and suppresses an elevated HR. The negative chronotropic effect of Efonidipine decreases heart rate, myocardial oxygen demand and increases coronary blood flow.
• Efonidipine increases coronary blood flow by blocking L & T-type calcium channels and attenuates myocardial ischaemia.
• By reducing synthesis and secretion of aldosterone, Efonidipine prevents hypertrophy and remodeling of cardiac myocytes.
• Efonidipine increases glomerular filtration rate without increasing intra-glomerular pressure and filtration fraction. This prevents hypertension induced renal damage.
• Efonidipine prevents Rho-kinase and NF-kB induced renal parenchymal fibrosis and provides long term renal protection.
• Efonidipine suppresses renin secretion from the Juxta Glomerular apparatus in the kidneys. •Efonidipine enhances sodium excretion from the kidneys by suppressing aldosterone synthesis and secretion from the adrenal glands. Aldosterone induced renal parenchymal fibrosis is suppressed by Efonidipine. •Efonidipine prevents NF-kB induced hypertrophy and inflammation in the renal vasculature and protects the kidneys.
• Efonidipine protects against endothelial dysfunction due to its anti-oxidant activity and by restoring nitric oxide bioavailability.
• Efonidipine has anti-atherogenic activity and protects the blood vessels from atherosclerosis.
• Efonidipine lowers blood pressure in cerebral resistance vessels and prevents hypertension induced brain damage.

5.3 Pharmacokinetic properties

Absorption

Peak plasma concentration is achieved in about 1.5 to 3.67 hours after administration. The bioavailability of Efonidipine is ~25% and half-life is approximately 4 hours.

Efonidipine 40mg when administered to healthy volunteers under fasting conditions shows the following pharmacokinetic profile:

The dissociation constant of Efonidipine from dihydropyridine receptors is very low (0.0042/min/nM), signifying very slow dissociation from the receptors. This explains the long duration of action of Efonidipine.

Metabolism

Efonidipine is primarily metabolized in the liver. The important metabolites are N-dephenylated Efonidipine (DPH), deaminated Efonidipine (AL) and N-debenzylated Efonidipine (DBZ). DBZ and DPH exhibit activity as calcium antagonists. The vasodilating properties of DBZ and DPH were about two-thirds and one-third respectively than that of the parent compound. Results suggest that the majority of the pharmacological effect after oral dosing of Efonidipine hydrochloride in man is due to unchanged compound and its metabolites make a small contribution to the pharmacological effect.

Elimination

Biliary route is the main pathway of excretion. No significant amount of unchanged drug is excreted in urine. In the urine collected for 24 h after an oral dosing, 1.1% of the dose was excreted as deaminated Efonidipine, and 0.5% as a pyridine analogue of deaminated Efonidipine.

6.1 Animal Toxicology or Pharmacology

The acute toxicology of efonidipine was studied in male and female mice, rats, and dogs following oral or intravenous administration. The intravenous LD, values in male mice and rats were 77 and 51 mg/kg, respectively. The oral LD, values for efonidipine in mice, rats, and dogs were higher than 1,500 mag. The signs of toxicity observed in mice and rats were depression of spontaneous movement, hypothermia, sedation, piloerection, lying, gasping, and clonic convulsion. The dogs developed mild diarrhea, soft stools, or a temporary decrease in food consumption.

A 13-week oral subacute toxicity study of efonidipine was performed in male or female rats and dogs. Increases in water consumption and urine volume were observed in male and female rats receiving efonidipine at 300 mg/kg/day. Urinalysis revealed a high concentration of Na+ and C1- in the rats receiving 100 or 300 mg/kg/day. Organ weight measurement revealed an increase in liver and heart weight in male animals receiving 10 mg/kg/day or more and in female animals receiving 30 mg/kg/day or more.

Thus, in this study, the noneffective dose level was 3 mg/kg/day in rats. The effects observed at 300 or 100 mg/kg/day in groups of male or female dogs included reversible hyperemia of the sclera. Pathological examination revealed a dose-induced increase in the absolute and relative heart weight in female dogs treated with the drug at 100 mg/kg/day or more. Thus, the maximum noneffective dose of efonidipine in dogs of either sex was estimated to be around 30 mg/kg/day.

An oral chronic toxicity study of efonidipine was carried out in rats and dogs. Efonidipine was administered to rats at a daily dose of 1.5, 7, or 30 mg/kg for one year.

Organ weight measurement revealed an increase or a tendency of increase in heart weight in male or female rats receiving 30 mg/kg/day. A decreased thyroid weight in the males and an elevated liver weight in the females were found in the 30 mg/kg/day group.

Therefore, the noneffective estimated oral dose of efonidipine in rats was 7 mg/kg/day. Efonidipine in a gelatin capsule containing 2.0, 6.5, or 20 mg/kg/day was administered to dogs once daily for one year. The estimated effective dose was ca 20 mg/kg/day and the noneffective dose was ca 6.5 mg/kg/day

Efonidipine is a novel dihydropyridine calcium channel blocker having anti-hypertensive and anti-anginal properties.

Chemical name: (±) -2 - [benzyl (phenyl) amino] ethyl 1, 4-dihydro-2 ,6-dimethyl- 5-(5,5-dimethyl-2-oxo-1 ,3,2-dioxaphosphorinan-2-yl) -4 - (3-nitrophenyl) -3-pyridinecarboxylate hydrochloride ethanol.

Molecular formula: C34H38 N3O7P • HCl •C2H6O

Molecular mass: 714.18 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 Blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store below 25°C. Protected from light & moisture.
• Keep out of reach of children.

Efnocar is a type of medicine known as a calcium channel blocker (CCB). It is used to treat high blood pressure (hypertension) and a type of chest pain called angina. It can be used by itself or with other medicines to treat these conditions. Do not use Efnocar if you are allergic to efonidipine (the active ingredient in Efnocar), or to the inactive ingredients.

Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies. Tell your doctor if you:

• ever had heart disease
• ever had liver problems
• are pregnant, or plan to become pregnant.
• are breast-feeding. Do not breast-feed while taking Efnocar.

You can stop breast-feeding or take a different medicine.

It may be easier to take your dose if you do it at the same time every day, such as with breakfast or dinner, or at bedtime.

While you are taking Efnocar do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor.

09/10/2024

Buprenorphine Transdermal Patch

BuprePLAST 5 mcg/hr

Each 6.25 cm2 transdermal patch contains :

Buprenorphine Ph.     Eur. 5 mg

Excipients     q.s.

Each patch delivers 5 mcg/hr Buprenorphine

BuprePLAST 10 mcg/hr

Each 12.5 cm2 transdermal patch contains :

Buprenorphine Ph. Eur.    10 mg

Excipients    q.s.

Each patch delivers 10 mcg/hr Buprenorphine

Transdermal Patch

4.1 Therapeutic indication

For the treatment of severe opioid responsive pain conditions which are not adequately responding to nonopioid analgesics.

4.2 Posology and method of administration

Bupreplast patch should be administered every 7th day. Bupreplast patch is not suitable for the treatment of acute pain.

Patients aged 18 years and over

The lowest Bupreplast patch dose (Bupreplast 5 mcg/hr transdermal patch) should be used as the initial dose. Consideration should be given to the previous opioid history of the patient as well as to the current general condition and medical status of the patient.

Titration

During initiation and titration with Bupreplast, patients should use the usual recommended doses of short acting supplemental analgesics as needed until analgesic efficacy with Bupreplast patch is attained. The dose should not be increased before 3 days, when the maximum effect of a given dose is established. Subsequent dosage increases may then be titrated based on the need for supplemental pain relief and the patient's analgesic response to the patch.

To increase the dose, a larger patch should replace the patch that is currently being worn, or a combination of patches should be applied in different places to achieve the desired dose. It is recommended that no more than two patches are applied at the same time, regardless of the patch strength. A new patch should not be applied to the same skin site for the subsequent 3-4 weeks. Patients should be carefully and regularly monitored to assess the optimum dose and duration of treatment.

Conversion from opioids

Patch can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (Bupreplast 5 mcg/hr transdermal patch) and continue taking short-acting supplemental analgesics during titration as required.

Patients under 18 years of age

As buprenorphine patch has not been studied in patients under 18 years of age,the use of Bupreplast patch in patients below this age is not recommended.

Elderly

No dosage adjustment of Bupreplast patch is required in elderly patients.

Renal impairment

No special dose adjustment of Bupreplast patch is necessary in patients with renal impairment.

Hepatic impairment

Buprenorphine is metabolised in the liver. The intensity and duration of its action may be affected in patients with impaired liver function. Therefore patients with hepatic insufficiency should be carefully monitored during treatment with Bupreplast patch. Patients with severe hepatic impairment may accumulate buprenorphine during Bupreplast patch treatment. Consideration of alternate therapy should be considered, and Bupreplast should be used with caution, if at all, in such patients.

Patch application

Bupreplast should be applied to non-lrritated, Intact skin of the upper outer arm, upper chest, upper back or side of the chest, but not to any parts of the skin with large scars. Bupreplast patch should be applied to a relatively hairless or nearly hairless skin site. If none are available, the hair at the site should be cut with scissors, not shaven.

If the application site must be cleaned, It should be done with clean water only. Soaps, alcohol, oil, lotions of abrasive devices must not be used. The skin must be dry before the patch is applied. Bupreplast should be applied immediately after removal from the sealed sachet. Following removal of the protective layer, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges. If the edges of the patch begin to peel off, the edges may be taped down with suitable skin tape.

The patch should be worn continuously for 7 days.

Bathing, showering, or swimming should not affect the patch. If a patch falls off, a new one should be applied.

Duration of administration

Bupreplast should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Bupreplast is necessary in view of the nature and severity to the illness, then careful and regular monitoring should be carried out (If necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.

Discontinuation

After removal of the patch, buprenorphine serum concentrations decrease gradually and thus the analgesic effect is maintained for a certain amount of time. This should be considered when therapy with Bupreplast is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of the patch. At present, only limited information is available on the starting dose of other opioids administered after discontinuation of the transdermal patch.

Patients with fever or exposed to external heat

While wearing the patch, patients should be advised to avoid exposing the application site to external heat sources, such as heating pads, electric blankets, heat lamps, sauna, hot tubs, and heated water beds, etc., as an increase in absorption of buprenorphine may occur. When treating febrile patients, one should be aware that fever may also increase absorption resulting in increased plasma concentrations of buprenorphine and thereby increased risk of opioid reactions.

4.3 Contraindications

Buprenorphine patch is contraindicated in :

• Patients with known hypersensitivity to the active substance buprenorphine or to any of the excipients.
• The treatment of opioid dependence and narcotic withdrawal.
• Conditions in which the respiratory centre and function are severely impaired or may become so.
• Patients who are receiving MAO inhibitors or have taken them within the last two weeks.
• Patients suffering from myasthenia gravis
• Patients suffering from delirium tremens
• Pregnancy (see "Warnings & Precautions").

4.4 Special warnings and precautions for use

• Buprenorphine should be used with particular caution in patients with acute alcohol intoxication, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure, or in patients with severe hepatic impairment.
• Buprenorphine may lower the seizure threshold in patients with a history of seizure disorder.
• Significant respiratory depression has been associated with buprenorphine, particularly by the intravenous route. A number of overdose deaths have occurred when addicts have intravenously abused buprenorphine, usually with benzodiazepines concomitantly. Additional overdose deaths due to ethanol and benzodiazepines in combination with buprenorphine have been reported.
• Since CYP3A4 inhibitors may increase concentrations of buprenorphine, patients already treated with CYP3A4 inhibitors should have their dose of Buprenorphine carefully titrated since a reduced dosage might be sufficient in these patients.
• Buprenorphine is not recommended for analgesia in the immediate post-operative period or in other situations characterised by a narrow therapeutic index or a rapidly varying analgesic requirement.
• Controlled human and animal studies indicate that buprenorphine has a lower dependence liability than pure agonist analgesics. In humans limited euphorigenic effects have been observed with buprenorphine. This may result in some abuse of the medicinal product and caution should be exercised when prescribing to patients known to have, or suspected of having, a history of drug abuse or alcohol abuse or serious mental illness.
• As with all opioids chronic use of buprenorphine can result in the development of physical dependence. Withdrawal (abstinence syndrome), when it occurs, is generally mild, begins after 2 days and may last up to 2 weeks. Withdrawal symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.
• Athletes should be aware that this medicine may cause a positive reaction to sports doping control tests.
• Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs : Concomitant use of Buprenorphine and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Buprenorphine concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
• The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms.

Serotonin syndrome

Concomitant administration of Buprenorphine and other serotonergic agents, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition.

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

4.5 Drugs interactions

Buprenorphine must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous two weeks. Effect of other active substances on the pharmacokinetics of buprenorphine :

• Buprenorphine is primarily metabolised by glucuronidation and to a lesser extent (about 30%) by CYP3A4.
• Concomitant treatment with CYP3A4 inhibitors may lead to elevated plasma concentrations with intensified efficacy of buprenorphine.
• Studies with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following buprenorphine with ketoconazole as compared to buprenorphine alone.
• The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied.
• Co-administration of buprenorphine and enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin and rifampicin) could lead to increased clearance which might result in reduced efficacy.
• Reductions in hepatic blood flow induced by some general anaesthetics (e.g. halothane) and other medicinal products may result in a decreased rate of hepatic elimination of buprenorphine.

Pharmacodynamic interactions

Buprenorphine should be used cautiously with :

• Other central nervous system depressants : other opioid derivatives (analgesics and antitussives containing e.g. morphine, dextropro-poxyphene, codeine, dextromethorphan or noscapine). Certain anti-depressants, sedative H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances. These combinations increase the CNS depressant activity. Benzodiazepines : This combination can potentiate respiratory depression of central origin.
• At typical analgesic doses buprenorphine is described to function as a pure mu receptor agonist. In buprenorphine clinical studies subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to buprenorphine. There were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to buprenorphine.
• Sedative medicines such as benzodiazepines or related drugs The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited Co-administration of Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased.

4.6 Use in special populations

Pregnancy

There are no or limited amount of data from the use of buprenorphine in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Prolonged use of buprenorphine during pregnancy can result in neonatal opioid withdrawal. Therefore, buprenorphine should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.

Nursing Mothers

Buprenorphine is excreted in human milk. Studies in rats have shown that buprenorphine may inhibit lactation. Available pharmacodynamic / toxicological data in animals has shown excretion of buprenorphine in milk. Therefore, the use of buprenorphine during lactation should be avoided.

Fertility

No human data on the effect of buprenorphine on fertility are available. In a fertility and early embryonic development study, no effects on reproductive parameters were observed in male or female rats

4.7 Effects on ability to drive and use machines

Buprenorphine has major influence on the ability to drive and use machines. Even when used according to instructions, buprenorphine patch may affect the patient's reactions to such an extent that road safety and the ability to operate machinery may be impaired. This applies particularly in the beginning of treatment and in conjunction with other centrally acting substances including alcohol, tranquillisers, sedatives and hypnotics. An individual recommendation should be given by the physician. A general restriction is not necessary in cases where a stable

dose is used.

In patients who are affected, such as during treatment initiation or titration to a higher dose, these patients should not drive or use machines, nor for at least 24 hours after the patch has been removed.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. When prescribing this medicine, patients should be told :

• The medicine is likely to affect your ability to drive.
• Do not drive until you know how the medicine affects you.

4.8 Undesirable effects

Serious adverse reactions that may be associated with buprenorphine patch therapy in clinical use are similar to those observed with other opioid analgesics, including respiratory depression (especially when used with other CNS depressants) and hypotension. The following undesirable effects have occurred :

Very common (> 1/10, common (> 1/100, <1/10, uncommon (>/1000, < 1/100), rare (> 1/10,000 < 1/1000), very rare (< 1/10,000 including isolated reports).

Immune system disorders

Uncommon : hypersensitivity

Very rare : anaphylactic reaction, anaphylactoid reaction

Metabolism and nutrition disorders

Common : anorexia

Uncommon : dehydration

Psychiatric disorders

Common : confusion, depression, insomnia, nervousness

Uncommon : sleep disorder, restlessness, agitation, depersonalization, euphoric mood, affect lability, anxiety, hallucinations, nightmares

Rare : psychotic disorder, decreased libido

Very rare : drug dependence, mood swings

Nervous system disorders

Very common : headache, dizziness, somnolence Common: paresthesia Uncommon : sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, tremor, abnormal coordination, disturbance in attention

Rare : balance disorder, speech disorder Very rare: involuntary muscle contractions

Eye disorders

Uncommon : dry eye, blurred vision

Rare : visual disturbance, eyelid oedema, miosis

Ear and labyrinth disorders

Uncommon : tinnitus, vertigo

Very rare : ear pain

Cardiac disorders

Uncommon : angina pectoris, palpitations, tachycardia

Vascular disorders

Common : vasodilation

Uncommon : hypotension, circulatory collapse, hypertension, flushing

Respiratory, thoracic and mediastinal disorders

Common : dyspnoea

Uncommon : asthma aggravated, cough, hypoxia, rhinitis, wheezing, hyperventilation, hiccups Rare: respirator y depression, respirator y failure

Gastrointestinal disorders

Very common : constipation, dry mouth, nausea, vomiting

Common : abdominal pain, diarrhoea, dyspepsia

Uncommon : flatulence

Rare : diverticulitis, dysphagia, ileus

Hepatobiliary disorders

Rare : Biliary colic

Skin and subcutaneous tissue disorders

Very common : pruritus, erythema

Common : rash, sweating, exanthema

Uncommon : dry skin, face oedema, urticaria Very rare : pustules, vesicles

Musculoskeletal and connective tissue disorders

Uncommon : Muscle cramp, myalgia, muscular weakness, muscle spasms

Renal and urinary disorders

Uncommon : urinary retention, micturition disorders

Reproductive system and breast disorders

Rare : erectile dysfunction, sexual dysfunction

General disorders and administration site conditions

Very common : application site pruritus, application site reaction

Common : tiredness, asthenia pain, peripheral oedema, application site reaction, erythema at site, rash at site, oedema, chest pain

Uncommon : fatigue, influenza like illness, pyrexia, rigors, malaise, oedema, drug withdrawal syndrome

Rare : application site inflammation

Investigations

Uncommon : alanine aminotransferase increased, weight decreased

Injury, poisoning and procedural complications

Uncommon : Accidental injury fall

* In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases treatment with buprenorphine patch should be terminated.

Buprenorphine has a low risk of physical dependence. After discontinuation of buprenorphine patch, withdrawal symptoms are unlikely. This may be due to the very slow dissociation of buprenorphine from the opioid receptors and to the gradual decrease of buprenorphine plasma concentrations (usually over a period of 30 hours after removal of the last patch). However, after long-term use of buprenorphine patch, withdrawal symptoms similar to those occurring during opioid withdrawal, cannot be entirely excluded. These symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia tremor and gastrointestinal disorders.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to :medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

Very common : headache, dizziness, somnolence Common: paresthesia Uncommon : sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, tremor, abnormal coordination, disturbance in attention Rare : balance disorder, speech disorder Very rare: involuntary muscle contractions

4.9 Overdose

Symptoms : Symptoms similar to those of other centrally acting analgesics are to be expected. These include respiratory depression, sedation, drowsiness, nausea, vomiting, cardiovascular collapse and marked miosis.

Treatment : Remove any patches from the patient's skin. Establish and maintain a patent airway, assist or control respiration as indicated and maintain adequate body temperature and fluid balance. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

A specific opioid antagonist such as naloxone may reverse the effects of buprenorphine. The dose of naloxone may be in the range 5 to 12 mg intravenously.

5.1 Mechanism of action

Buprenorphine is a partial agonist opioid, acting at the mu opioid receptor. It also has antagonistic activity at the kappa opioid receptor.

5.2 Pharmacodynamic properties

Buprenorphine can displace or block morphine binding to µ-receptor thus contributes to reduced opioid dependence. Buprenorphine agonist activity on µ receptor is the primary contributing factor to its analgesic signaling events. Buprenorphine interacts with nociceptin / ORL1 with much lower affinity and thus is unlikely to contribute to analgesic effects at therapeutic doses. Buprenorphine is a potent antagonist of κ-opioid receptor and this interaction could contribute to reduced tolerance and antidepressant like activity.

5.3 Pharmacokinetic properties

There is evidence of enterohepatic recirculation.

Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers. Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration. After intramuscular or oral administration buprenorphine apparently accumulates in the foetal gastrointestinal lumen - presumably due to biliary excretion, as enterohepatic circulation has not fully developed. Each patch provides a steady delivery of buprenorphine for up to seven days. Steady state is achieved during the first application. After removal of buprenorphine, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10 - 24 h).

Absorption

Following buprenorphine application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for “buprenorphine 10 microgram/hour” to deliver detectable buprenorphine concentrations (25 picograms/ml) was approximately 17 hours. Analysis of residual buprenorphine in patches after 7-day use shows 15% of the original load delivered. A study of bioavailability, relative to intravenous administration, confirms that this amount is systemically absorbed. Buprenorphine concentrations remain relatively constant during the 7-day patch application.

Application site

A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by buprenorphine is similar when applied to upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). The absorption varies to some extent depending on the application site and the exposure is at the most approximately 26 % higher when applied to the upper back compared to the side of the chest.

In a study of healthy subjects receiving buprenorphine repeatedly to the same site, an almost doubled exposure was seen with a 14-day rest period. For this reason, rotation of application sites is recommended, and a new patch should not be applied to the same skin site for 3-4 weeks. In a study of healthy subjects, application of a heating pad directly on the transdermal patch caused a transient 26 - 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hours after the heat was removed. For this reason, applying direct heat sources such as hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a buprenorphine site immediately after patch removal did not alter absorption from the skin depot.

Distribution

Buprenorphine is approximately 96% bound to plasma proteins. Studies of intravenous buprenorphine have shown a large volume of distribution, implying extensive distribution of buprenorphine. In a study of intravenous buprenorphine in healthy subjects, the volume of distribution at steady state was 430 l, reflecting the large volume of distribution and lipophilicity of the active substance.

Following intravenous administration, buprenorphine and its metabolites are secreted into bile, and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be approximately 15% to 25% of concurrent plasma concentrations.

Biotransformation and elimination

Buprenorphine metabolism in the skin following buprenorphine application is negligible. Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes, results in two primary metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before elimination. Buprenorphine is also eliminated in the faeces. In a study in post-operative patients, the total elimination of buprenorphine was shown to be approximately 551/h. Norbuprenorphine is the only known active metabolite of buprenorphine.

Effect of buprenorphine on the pharmacokinetics of other active substances

Based on in vitro studies in human microsomes and hepatocytes, buprenorphine does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of buprenorphine 20μg/h transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.

6.1 Animal toxicology or pharmacology

Systemic toxicity and dermal toxicity

In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, buprenorphine caused minimal or no adverse systemic events, whereas skin irritation was observed in all species examined. Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.

Reproductive and developmental toxicity

No effect on fertility or general reproductive performance was observed in rats treated with buprenorphine. In embryofoetal developmental toxicity studies conducted in rats and rabbits using buprenorphine, no embryofoetal toxicity effects were observed. In a rat pre- and post-natal developmental toxicity study with buprenorphine there was pup mortality, decreased pup body weight and concomitant maternal reduced food consumption and clinical signs.

Genotoxicity

A standard battery of genotoxicity tests indicated that buprenorphine is non-genotoxic.

Carcinogenicity

In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.

Buprenorphine is a semi synthetic derivative of an opiate alkaloid thebaine that is isolated from the poppy Papaver somniferum. Buprenorphine is a hydrophobic molecule and carries a complex chemical structure with multiple chiral centers.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A pouch of 1 patch.

8.4 Storage and handling instructions

Store in a cool & dry place. Protect from light & moisture.

Keep out of reach of children.

• These patches contain a strong pain killer.
• Ensure that old patches are removed before applying a new one.
• Patches must not be cut.
• Do not expose the patches to a heat source (such as a hot water bottle).
• Do not soak in a hot bath or take a hot shower whilst wearing a patch.
• If you develop a fever tell your doctor immediately.
• Follow the dosage instructions carefully and only change your patch on the same day and at the same time 7 days later.
• If your breathing becomes shallow and weak take the patch off and seek medical help.

21 August 2024

Eclipta alba, Andrographis paniculata, Cyprus rotendus, Tinospora cardifolia, Silybum marianum, Terminalia arjuna, Phyllanthus niruri, Emblica officianalis, Terminalia chebula Piper longum and Terminalia bellirica syrup

Each 10 ml of syrup contains extract:

Eclipta alba (Whole Plant) ……………………………. 125 mg

Andrographis paniculata (Whole Plant) …………………………………………………. 25 mg

Tinospora cardifolia (Stem)……………………………… 25 mg

Cyprus rotendus (Rhizome)………………………………. 50 mg

Silybum marianum (Whole Plant) ……………………. 35 mg

Terminalia arjuna (Bark)…………………………………… 50 mg

Phyllanthus niruri (Whole Plant) ………………………. 150 mg

Emblica officianalis (Fruit Pulp) …………………………. 50 mg

Terminalia chebula (Fruit Pulp) ………………………… 25 mg

Piper longum (Root)…………………………………………. 10 mg

Terminalia bellirica (Fruit Pulp) …………………………. 25 mg

Excipients & Flavours q.s.

Preservatives: Methylparaben Sodium & Propylparaben Sodium

Syrup, 150 ml

4.1 Therapeutic indication

• Jaundice
• Anorexia / Loss of appetite
• Alcholic liver disease

4.2 Posology and method of administration

2 teaspoonfuls (10 ml) three times daily or as directed by the Physician.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in the formulation.

4.4 Special warnings and precautions for use

No known warnings and precautions

4.5 Drugs interactions

No Clinically significant drug-drug interaction has been reported with Boostaliv syrup.

4.6 Use in special populations

Usage in pregnancy & lactation

Pregnant and lactating women should consult physician before starting treatment with Boostaliv syrup.

Usage in pediatrics

Physician supervision needed before starting treatment with Boostaliv syrup.

4.7 Effects on ability to drive and use machines

It is not known whether Boostaliv syrup alters the ability to drive. Do not drive if you experience any symptoms that affect your ability to concentrate and react.

4.8 Undesirable effects

There were no reported or observed significant adverse effects with Boostaliv syrup. However, mild side effects like nausea, gastritis, headache, bodyache, constipation, and insomnia have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

No data on overdosage of this product. Available clinical studies demonstrate that Boostaliv syrup is safe and no significant adverse or toxic effects of Boostaliv syrup are observed in humans

5.1 Pharmacodynamic properties

Eclipta Alba

Eclipta Alba is considered a powerful liver tonic. It elevates the activity of antioxidant enzymes SOD, CAT,GSH. Eclipta Alba has shown protective effect on experimental liver damage in rats and mice and also used for the treatment of liver cirrhosis and infective hepatitis by reducing centrilobular necrosis, hydropic degeneration and fatty change of the hepatic parenchymal cells. Eclipta Alba improves the both enzymatic and non-enzymatic antioxidant status.

Tinospora cordifolia

T. cordifolia played an important role in relieving the symptoms as well as normalization of altered liver function test when studied its effect against hepatotoxin CCl4. It is studied against the hepatic damage induced by a standard hepatotoxin – carbon tetra chloride (CCl4). T. cordifolia, it was proved to be effective in preventing fibrous changes and promoting regeneration by paranchymal tissue.

Andrographis paniculata

Andrographolide is extensively used as a stimulating agent for liver enzymes and hepatoprotective agent. Andrographolide increases the bile flow and bile salt production. Studies showed that Andrographolide is a potent hepatoprotective agent when compared with silymarin. Oral administration of the aqueous extract of plant in different doses caused a significant elevation of catalase, superoxide dismutase and glutathione-s-transferase (GSH) activities. It is a potent radical scavenging agent against various pathophysiological oxidants.

Cyprus rotendus

Rhizomes of C. rotundus (Cyperaceae) were evaluated for hepatoprotective activity in rats by inducing liver damage by carbon tetrachloride. It showed significant protective effect by lowering serum levels of liver enzymes like glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, alkaline phosphatase and total bilirubin. It also showed positive changes on histopathology. Clinical studies have suggested that the gastroprotective action of C. rotundus is related to its inhibition of gastric motility and endogeneous prostaglandins.

Terminalia arjuna

T.arjuna demonstrated the hepatoprotective and antioxidant effect of Terminalia arjuna aqueous bark extract against Isoniazid induced hepatotoxicity. T.arjuna demonstrated the hepatoprotective and antioxidant effect of Terminalia arjuna aqueous bark extract against Isoniazid induced hepatotoxicity. Terminalia arjuna shows potential antioxidant and free radical scavenging activity due to presence of more amount of flavonoid and phenolic content. It significantly reduces the elevated levels of biochemical markers like SGPT, SGOT, ALP, ACP, Bilirubin. Plant extract treatment also increased the level of SOD and GSH.

T. bellirica

T. bellirica as a whole or its specific components possess ethnomedicinal attributes and are used in various herbal formulations. It is used as astringent, laxative, antipyretic, and anthelmintic agent. Fruits are useful in the treatment of asthma, bronchitis, hepatitis, diarrhea, piles, dyspepsia, eye diseases, hoarseness of voice, and scorpion-sting and also used as hair tonic. Fruit pulp is used in dysenteric-diarrhea, leprosy, piles, and dropsy.

Piper longum

Piperine is the major and active constituent of long pepper (Piper longum). Piperine as the world’s first bioavailability enhancer. Bioenhancers are such agents, which by themselves are not therapeutic entities but when combined with an active drug lead to the potentiation of the pharmacologic effect of the drug. Such formulations have been found to increase the bioavailability/bio efficacy of a number of drugs even when reduced doses of drugs are present in such formulations. Piperine increases the bioavailability, blood levels and efficacy of a number of drugs including ingredients of vasaka leaves, vasicine, sparteine, rifampicin, phenytoin, sulfadiazine and propranolol. It increases biavailability of silymarin. Thus dose required is lesser as compared to other silymarin preparations. It makes Boostaliv more potent at lower doses of silymarin.

Emblica officinalis

Hepatoprotective activity of emblica officinalis (EO) extracts was studied using carbon tetrachloride (CCI (4)) induced liver injury model in rats. It was found to inhibit the hepatotoxicity produced by acute and chronic CCI (4) administration as seen from the decreased levels of serum and liver lipid peroxides (LPO), glutamate-pyuvate transminase (GPT), and alkaline phosphatase (ALP). Chronic CCI (4) administration was also found to produce liver fibrosis as seen from the increased levels of collagen hydroxyproline and pathological analysis EO was found to reduce the elevated levels significantly, indicating that the extract could inhibit the induction of fibrosis in rats.

Phyllanthus niruri

The antioxidant hepatoprotective activity of P. niruri may be due to its rich content of flavonoids, tannins, lignans and terpenes, which possess antioxidative traits. It inhibits lipid peroxidation and prevent excessive superoxide synthesis. P. niruri may alleviate lipoprotein metabolism abnormalities, reduce cholesterol–phospholipid ratios, control biomembrane damage and decrease ROS-linked lipid peroxidation. It is also a potent NO-quenching agent.

This herb has been shown to significantly restore the reduced levels of GSH and various antioxidant enzymes and lower lipid peroxidation.

Studies focusing on the in-vivo hepatoprotective activity of P. niruri against paracetamolinduced hepatotoxicity observed the normalization of liver enzyme profiles. It also has hepatoprotective action against hepatotoxin like carbon tetrachloride.

Silybum marianum

Silymarin can inhibit the hepatic cytochrome P450 (CYP) detoxification system (phase I metabolism). This effect could explain some of the hepatoprotective properties of Silymarin, especially against the intoxication due to A. phalloides. The Amanita toxin becomes lethal for hepatocytes only after having been activated by the CYP system. Inhibition of toxin bioactivation may contribute to the limitation of its toxic effects. Additionally, silymarin, together with other antioxidant substances, could contribute towards protection against free radicals generated by enzymes of the CYP system.

Terminalia chebula

Terminalia chebula has been demonstrated to possess multiple pharmacological and medicinal activities, such as antioxidant, antimicrobial, antidiabetic, hepatoprotective, anti-inflammatory, antimutagenic, antiproliferative, radioprotective, cardioprotective, antiarthritic, anticaries, gastrointestinal motility and wound healing activity.

5.2 Pharmacokinetic properties

Andrographis paniculata

After giving ethanolic extract solid dispersion tablet (equivalent to 50 mg/Kg) to rats, the Cmax is 27.24±3.23 µg/mL with Tmax is of 1 hr. The Plasma half-life T1/2 11.74 ± 0.04 hr with AUC0- t and AUC0-α are 84.3±10.04 µg/mL, 420.0±32.2 µg.h/mL.

Silybum marianum

Silymarin is not soluble in water and is usually administrated in an encapsulated form. It is absorbed when given orally. Peak plasma concentration achieved in 6-8 hr. oral absorption of Silymarin is only about 23-47%, leading to low bioavailability of the compound. After oral administration the recovery of bile ranges from 2-3%. Silybin and the other components of Silymarin are rapidly conjugated with sulfate and glucoronic acid in liver and excreted through the bile.

Emblica officinalis

After giving 70 mg Emblica officinalis extract tablet to rabbits, the Cmax is 4.59±0.95µg/mL with Tmax is of 1.5±0.53 hr. The T1/2 is 6.0±0.33 hr, AUC0-24 and AUC0-∞ are 29.65±1.01 µg/mL, 32.60±1.02 µg.h/mL.

Eclipta alba

E. alba was found to be a strong inhibitor of CYP1A2 both in vitro and in vivo and may lead to serious herb-drug interaction if co-administered with other drugs that are metabolized by this enzyme.

Tinospora cordifolia

Tinospora cordifolia acts as immunomodulator by enhancing IgG antibodies, antifibrotic by hepatic regeneration, membrane stabilization, and Kupffer cell activation.

Terminalia arjuna

In vitro data indicated that the Terminalia arjuna extract contains constituents that can potentially inhibit the CYP3A and CYP2D isoenzymes which may in turn lead to pharmacokinetic drug–herb interaction.

Phyllanthus niruri

Phyllanthus amarus significantly inhibits the Metabolism of CYPA5 and CYPA7 enzymes which are essential enzymes responsible for phase 1 drug metabolism. Co-administration of Phyllanthus amarus with orthodox drugs that are completely metabolized by CYP3A Family can lead to therapeutic failure, drug interaction and adverse effect since it will interferes with it metabolism. Another study showed that CYP1A2, CYP2C9, CYP2D6 AND CYP3A4 enzymes were inhibited by aqueous extract of Phyllanthus amarus similarly human and rat glutathione S-transferases (GSTS) liver cytosolic enzyme was strongly inhibited by Phyllanthus amarus.

Terminalia bellirica (TB)

TB enhanced the differentiation of 3T3-L1 (mouse) cells to mature adipocytes and that one of the active main components was identified as gallic acid. Gallic acid (10–30 µM) enhanced the expression and secretion of adiponectin via adipocyte differentiation and also that of fatty acid binding protein-4, which is the target of peroxisome proliferator-activated receptor gamma (PPARγ), although it does not alter the expression of the upstream genes PPARγ and CCAAT enhancer binding protein alpha.

Piper longum

P. longum‘s anti-inflammatory quality may be linked to G-protein coupled signalling process (Module-4). This module contains genes like GRK2 and GRK6. Inflammatory mediators modulate GRKs signaling either by transcription regulation or its degradation. GRK2 act as mediator in the pathway that causes inflammatory pain. Thus, targeting GRKS by P. longum could be the reason of its anti-inflammatory properties.

Cyprus rotendus

Phenolic compounds from plant source have been found to be anti-inflammatory, which may be related to inhibition of COX activity and to anti-oxidant activity. They are also known to be toxic to bacterial cells and inhibit their growth at high concentrations.

T.chebula

T.chebula showed statistically significant reduction in the level of serum cholesterol, TG, TL, LDL and VLDL. There was a statistically significant increase in the level of HDL. Supplementation of T.chebula lowered the serum TL, TG, LDL-C and VLDL-C in heart patients.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

Boostaliv syrup is the combination of Eclipta alba (Whole Plant), Andrographis paniculata (Whole Plant), Tinospora cardifolia (Stem), Cyprus rotendus (Rhizome), Silybum marianum (Whole Plant), Terminalia arjuna (Bark), Phyllanthus niruri (Whole Plant), Emblica officianalis (Fruit Pulp), Terminalia chebula (Fruit Pulp), Piper longum (Root), and Terminalia bellirica (Fruit Pulp).

Boostaliv is a polyherbal formulation of solubilized Silymarin along with potent hepatoprotective herbs which synerzise the activity. The ingredients exhibit potent hepatoprotective properties in hepatotoxicity. They restore the functional efficiency of the liver by protecting the hepatic parenchyma and promoting hepatocellular regeneration. The antiperoxidative activity prevents the loss of functional integrity of the cell membrane, maintains cytochrome P-450 (a large and diverse group of enzymes, which catalyze the oxidation of organic substances), hastens the recovery period and ensures early restoration of hepatic functions in infective hepatitis. It facilitates the rapid elimination of acetaldehyde and ensures protection from alcohol-induced hepatic damage. The Formulation also diminishes the lipotropic effect in chronic alcoholic hepatitis and prevents fatty infiltration of the liver. In precirrhotic conditions, arrests the progress of cirrhosis and prevents further liver damage.

Hepatocyte regeneration

Boostaliv individual ingredient has shown protective effect on experimental liver damage in preclinical and clinical studies. They can also be used for the treatment of liver cirrhosis and infective hepatitis by reducing centrilobular necrosis, hydropic degeneration and fatty change of the hepatic parenchymal cells.

Improve Liver Functions

Silymarin and other herbs can normalize serum bilirubin, aspartate aminotransferase and alanin-aminotransferase values, while it can decrease gamma-glutamyl transferase activity and procollagen III peptide level in patients with chronic alcoholic liver disease

Anti-Inflammatory Effect

Silymarin inhibits lipid peroxidation which is a mechanism responsible for progression of liver damage, development of fibrosis and eventually cirrhosis. The common effects of silymarin on hepatocytes are anti-inflammatory and antifibrotic effects, antioxidant action and modulation of intrahepatic metabolic pathways.

Silymarin works as a hepatoprotective via: (1) preventing entry of various toxins, e.g., alcohol, carbon tetracholoride and heavy metals, into hepatocytes; (2) stimulating protein synthesis with hepatocyte regeneration; (3) acting as a free-radical scavenger and antioxidant; and (4) modulating the immune response (5) Inhibition of Kupffer cell functions and leukotriene formation.

Potent Anti-hepatotoxic Activities

Silymarin inhibits the hepatic cytochrome P450 detoxification system. This is especially responsible for its hepatoprotective efficacy against Amanita phalloides poisoning and free radicals generated by enzymes of CYP450 system.It is also considered a potent inhibitor of human intestinal β-glucuronidase, blocking the release and reabsorption of free xenobiotics and their metabolites from their glucuronide conjugate. Combination of silymarin with potent herbs make Boostaliv protective agent against hepatotoxic chemicals and drugs.This polyherbal combination also proves to be potential as prophylactic antioxidative agents. Herbs have supporting literature in the hepatoprotective and antioxidant effect against Isoniazid induced hepatotoxicity.

Antioxidant effect

Silymarin and constituents of Boostaliv exerts antioxidant action and prevents the depletion of glutathione in liver disorders. These herbs antagonize the depletion of the 2 main detoxifying mechanisms – (Glutathione) GSH and superoxide dismutase (SOD), by reducing the free radical load, increasing GSH levels and stimulating SOD activity. It also inhibits free radical induced lipid peroxidation.

Improves appetite

In anorexia and less than optimal growth and weight gain, As a daily health supplement, Boostaliv improves appetite, digestion and assimilation processes and promotes weight gain.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

8.4 Storage and handing instructions

Store in a cool & dry place, away from direct sunlight. Do not refrigerate

• Follow your doctor's instructions on the dosage and duration of Boostaliv Syrup.
• Before using, read the directions on the label. Take it orally after measuring it.
• Before using, give it a good shake.
• Boostaliv Syrup can be taken with or without food, however It is best if you take it at the same time every day.

15.07.2024